Novel broad-spectrum inhibitors of bacterial methionine aminopeptidase

Rose, Jonathan A.; Lahiri, S. C.; McKinney, David C.; Albert, Robert; Morningstar, Marshall L.; Shapiro, Adam B.; Fisher, Stewart L.; Fleming, Paul R.

doi:10.1016/j.bmcl.2015.05.061

Cited by 7 publications

(4 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the difference in the substrate specificities of bacterial MetAP1, human MetAP1 and human MetAP2, the enzyme is a good target for antibacterial agents. 15,16 DNA gyrase is an enzyme within the class of topoisomerase (Type II topoisomerase) that relieves strain while double-stranded DNA is being unwound by helicase. This causes negative supercoiling of the DNA.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Docking Studies of Novel Furan-azetidinone Hybrids as Potential Inhibitors of Escherichia coli

Jays¹,

Mohan²,

Saravanan³

2019

IJPER

View full text Add to dashboard Cite

Escherichia coli is the predominant gram negative bacteria responsible for a variety of hospital-acquired infections and urinary tract infections. As the bacterial strains are rapidly acquiring resistance to the available antibiotics, there is a need to discover novel antibacterial agents with different scaffolds. In this study, sixteen novel furan derivatives containing the azetidinone moiety were designed and synthesized to arrive at potentially effective antibacterial agents. In silico antibacterial activity was carried out to identify the specificity of the furan derivatives for the antibacterial targets. Molecular docking studies were conducted on four antibacterial targets of E. coli; Dihydrofolate reductase, DNA gyrase, Enoyl reductase and methionine aminopeptidase. Energy minimization of title compounds was carried out and they were docked on to the active site of the enzymes. Ligands were ranked according to their docking scores and their binding energy with the enzyme. The results obtained for the molecular docking of the title compounds with enoyl reductase of E. coli is quite promising. The study suggests that compounds 4E and 4D are potential inhibitors of enoyl reductase and specifically bind to the enzyme.

show abstract

Section: Introductionmentioning

confidence: 99%

“…Bacterial DNA gyrase is the target of many antibiotics, including nalidixic acid, novobiocin and ciprofloxacin. [15][16][17] Novel Bacterial Topoisomerase Inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase. [17][18][19]…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking Studies of Novel Furan-azetidinone Hybrids as Potential Inhibitors of Escherichia coli

Jays¹,

Mohan²,

Saravanan³

2019

IJPER

View full text Add to dashboard Cite

show abstract

“…Compound IX possessed good inhibition against E. coli, H. influenza and S. pneumoniae MAP isozymes with IC 50 0.8 � 0.1 μM, 1.1 � 0.1 μM and 0.3 � 0.03 μM, respectively. [21] In the present work, we synthesized a library of 3,4-dihydro-1H-benzo [b]azepine-2,5-dione (X) derivatives and evaluated them for their anti-bacterial potential. These derivatives have shown good to moderate inhibition against S. aureus as well as Mtb.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antibacterial Evaluation of 3,4‐Dihydro‐1H‐benzo[b]azepine‐2,5‐dione Derivatives

et al. 2022

View full text Add to dashboard Cite

Fused-azepinones are interesting heterocyclic scaffolds present in various natural products and synthetic derivatives with potent kinase inhibition, anti-cancer, anti-inflammatory, anti-HIV, neuroprotective, anti-fouling and other biological activities. These fused-azepinones are also known for their antimicrobial activity against the Plasmodium falciparum, Leishmania, Escherichia coli, and Streptococcus pneumonia. In the present work, we synthesized a library of 3,4-dihydro-1Hbenzo[b]azepine-2,5-dione derivatives and evaluated them for their antibacterial potential against a panel of bacterial pathogens. The Structure-activity relationship studies revealed the essential structural features for the promising antibacterial properties against Staphylococcus aureus and Mycobacterium tuberculosis with MIC 4-64 μg/mL. In addition, these compounds exhibited favourable selectivity index (SI � 10) in cytotoxicity studies. With the interesting antibacterial properties exhibited and good selectivity index, these compounds have emerged as promising candidates for further development.

show abstract

“…Recently, methionine aminopeptidase (MetAP), a ubiquitous enzyme responsible for the cleavage of methionine initiatory residues from nascent proteins, has been suggested as a potential broad spectrum antibacterial target. 8 MetAP is a dinuclear metalloprotease, with demonstrated in vitro activity when Co, Mn, Fe, Zn, and Ni divalent cofactors are utilized. 9–11 Additionally, current inhibitory motifs demonstrate a significant correlation with cofactor identity and are generally only potent against enzymes binding specific metals.…”

mentioning

confidence: 99%

The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications

Helgren

Seven

Chen

et al. 2018

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a concentration of 10 µM and potential hits were determined to be those exhibiting greater than 50% inhibition of enzymatic activity. These hit compounds were then rescreened against the target in 8-point dose-response curves and 11 compounds were found to inhibit enzymatic activity with IC values of less than 10 µM. Finally, compounds (1-5) were docked against RpMetAP with AutoDock to determine potential binding mechanisms and the results were compared with crystal structures deposited within the PDB.

show abstract

Novel broad-spectrum inhibitors of bacterial methionine aminopeptidase

Cited by 7 publications

References 23 publications

Molecular Docking Studies of Novel Furan-azetidinone Hybrids as Potential Inhibitors of Escherichia coli

Molecular Docking Studies of Novel Furan-azetidinone Hybrids as Potential Inhibitors of Escherichia coli

Synthesis and Antibacterial Evaluation of 3,4‐Dihydro‐1H‐benzo[b]azepine‐2,5‐dione Derivatives

The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications

Contact Info

Product

Resources

About